THE OI REPORT: A Critical Review of the Treatment & Prophylaxis of AIDS-Related Opportunistic Infections (OIs)

MYCOBACTERIUM AVIUM COMPLEX
by Michael Marco & Tim Horn

INTRODUCTION
Disseminated disease due to Mycobacterium avium complex (MAC) is the most common systemic bacterial infection among patients with late-stage HIV disease (Horsburgh 1991). MAC organisms which cause disease in this patient population, primarily Mycobacterium avium and Mycobacterium intracellulare, are ubiquitous; they can be found in water, soil, foods, and a variety of animal species (Wolinsky 1968; Kirschner 1992; Von Reyn 1994). For most patients, there does not appear to be a consistent relationship between specific environmental exposure and the risk of developing MAC disease (Benson 1994; USPHS 1995). In fact, genetic relatedness between MAC species found in the environment and those found in humans has been difficult to establish (Morrissey 1993). However, Von Reyn and colleagues have reported that potable water in various hospitals was the source of MAC infection of some patients (Von Reyn 1994).

MAC organisms also cause disease in poultry and swine and are commonly excreted in the feces of birds (but not cattle or swine), after which the bacilli persist in the soil for long periods of time (Inderlied 1993). Although MAC organisms can occasionally be isolated from the stools of healthy humans, most are not associated with disease. Since the advent of the AIDS epidemic, however, immune deficiency due to HIV infection is the most common cause of MAC disease.

EPIDEMIOLOGY
In the early 1990s, the reported incidence of disseminated MAC (dMAC) disease in the United States ranged from 18% to 40% in patients with AIDS (Horsburgh 1991; Bacellar 1994). Since the wide-spread use of potent protease inhibitor combination therapy (PPICT) in mid-1996, the incidence rates of MAC in patients who have access to PPICT is approximately 2% (Currier 1997, Jouen 1997). Prior to the widespread use of chemoprophylaxis, MAC appeared to be on the rise (Bacellar 1994). The risk of dMAC increases with the degree of immunosuppression; the highest risk is associated with CD4 counts below 50. In a natural history study of 1,020 symptomatic, HIV-positive patients (CD4 count below 250) who were being treated with AZT, the incidence of MAC was 12% at one year and 19% at two years. MAC infection was defined as a positive sputum, blood, or tissue culture. Risk factors for developing dMAC included prior Pneumocystis carinii pneumonia (PCP), low baseline CD4 counts, low white blood cell count, and low hematocrit. CD4 counts lower than 100, severe anemia or PCP during follow-up, as well as interruption of AZT, were each associated with a greater risk of MAC infection (Chaisson 1992).

Colonization by MAC appears to predict an increased risk of disseminated disease. In a natural history study, Chin and colleagues demonstrated that in patients with CD4 counts below 50 who were cultured for mycobacteria every three months, colonization of the stool increased the risk of MAC sixfold and colonization of the sputum increased the risk twofold. In this study, however, disseminated MAC was not always preceded by detectable colonization; approximately two-thirds of patients who developed MAC bacteremia were not colonized. The sensitivity of induced sputum or stool cultures in identifying patients who became bacteremic was only 22% and 21%, respectively (Chin 1994). Similar findings were reported in a prospective evaluation of colonization of these sites in HIV-positive patients with CD4 counts below 200. Screened sputum cultures were positive for only 21% of those who became bacteremic (Brown 1993). Such studies indicate that routine screening for these sites is unlikely to be useful in identifying patients at increased risk (Brown 1993)

ETIOLOGY & PATHOGENESIS
The main portals of entry of MAC into the body are thought to be the respiratory and gastrointestinal (GI) tracts (Damsker 1985; Jacobson 1991; Horsburgh 1992b; Poropatich 1987, Chin 1994). Oropharyngeal colonization - as the result of ingestion of MAC-containing water or food - may serve as a reservoir from which the organism finds its way to either the lungs or GI tract. After initial infection, a brief dissemination of MAC may result in the secondary seeding of other sites. Subsequent progression of disease which is characterized by fluctuations in the level of MAC, occurs as the body loses its immune defenses. As the immune system continues to deteriorate, mycobacterial organisms replicate rapidly, leading to disseminated infection and disease (Kemper 1996). In immunocompetent patients with MAC infection, the lungs almost always appear to be the primary site of infection. In HIV-infected patients, however, MAC rarely causes pulmonary disease and often causes disease in the GI tract, suggesting that the latter route of infection predominates in immunocompromised patients (Jacobson 1991). Animal models inoculated through the GI developed disseminated disease, supporting this hypothesis (Bermudez 1992).

It is unclear whether MAC infection in HIV-positive patients results from recent acquisition of MAC or from reactivation of latent MAC infection. The incidence of dMAC does not vary among age groups (Horsburgh 1992b). Thus, reactivation of latent infection is unlikely; if it occurred, the incidence of dissemination would increase with age - much like tuberculosis, a disease primarily caused by a reactivation of latent infection. Others contend that MAC is a primary infection because HIV-positive patients with dMAC are generally unable to launch an antibody response to MAC (Wayne 1986).

In patients with fairly intact immune systems, the infection is quickly contained but remains dormant for months or years. MAC colonization in patients with moderately compromised immune systems may result in disease at the localized sites of infection (lungs, lymph nodes, or GI tract) (Benson 1993). However, localized MAC disease is not commonly observed in HIV-positive patients.

CLINICAL MANIFESTATIONS
Most patients with dMAC infection have CD4 counts below 50, and many have a history of previous OIs. The median CD4 count of patients with dMAC infection ranges from 10 to 20 (Horsburgh 1991; Nightingale 1992, 1993; Shafran 1996). Fewer than 5% of dMAC infections occur in patients with a CD4 counts above 50 (Chin 1994).

Fever, night sweats, progressive weight loss, wasting, abdominal pain and diarrhea, are the most frequently described signs and symptoms of dMAC. Hepatomegaly (enlargement of the liver) or splenomegaly (enlargement of the spleen), intra-abdominal lymphadenopathy (enlargement of the lymph nodes), an elevated serum alkaline phosphatase level and anemia are the most common signs and symptoms associated with dMAC (Kemper 1996).

A recent case-control study of 270 HIV infected persons with and without MAC indicated that "specific signs, symptoms and laboratory abnormalities are seen in persons with MAC ... before a positive MAC blood culture [which suggests] that bacteremia occurs after a period of localized infection." (Horsburgh 1995)

Predictors of MAC in a Case-Control Study
	MAC	No MAC	p-value
N	90	180	-
Hemoglobin (gm)	10.9	12.0	0.001
Fever	48%	26%	0.001
Weight (kg)	66.3	71.1	0.01
Karnofsky score	74.3	83.8	0.01
Abdominal pain	33%	22%	0.04
Diarrhea	37%	27%	0.07
Alkaline phosphatase	203	148	0.08

(Horsburgh 1995)

A variety of other manifestations may occur depending on the organs involved. Localized diseases due to MAC are less common, but do occur. Reported cases include pulmonary disease (Kerlikowske 1992), pericarditis (acute or chronic inflammation of the membranous sac surrounding the heart) (Gascon 1993), deep soft tissue abscesses and skin lesions (Clark 1993), osteomyelitis (inflammation of the bone marrow) (Owen 1993), diarrhea and malabsorption (Greenson 1991), or central nervous system involvement (Jacob 1993).

The Impact of MAC on Survival

Several case control studies have found that among patients matched by baseline CD4 and prior AIDS-defining illnesses, those with MAC died faster (Sathes 1990; Horsburgh 1991; Jacobson 1993). Patients were matched for baseline CD4 counts and prior AIDS-defining illnesses.

Impact of MAC on Survival in People with AIDS
Study	AIDS without MAC	AIDS with MAC
Sathes 1990	280 days	139 days
Horsburgh 1991	330 days	120 days
Jacobson 1993	275 days	107 days

These studies reflect the natural history during an era of no MAC prophylaxis, no standard treatment guidelines, and primitive antiretroviral therapy. Patients developing MAC in the mid 1990s are expected to live longer. The duration of survival after the diagnosis of MAC appeared to be generally consistent, with a reported range of 107 to 139 days. Severe anemia (hematocrit levels below 25%) was a significant independent negative predictor of survival among patients with MAC (Sathes 1990).

DIAGNOSIS

The diagnosis of dMAC requires recovery in culture of the organism from otherwise sterile body tissue or fluid: blood, liver, bone marrow, or cerebrospinal fluid. A single positive culture from one of these sites is sufficient to make the diagnosis of disseminated infection (Kemper 1996). Since Mycobacterium avium can take up to six weeks to be recovered on solid media, isolation of the mycobacteria in blood using radiometric detection techniques is the most frequent means of detecting MAC in HIV-positive patients. For this purpose, two different radiometric assays are available: the BACTEC radiometric method using liquid media, and the Septi-Chek system. According to one comparative study, the BACTEC radiometric method was the most sensitive and accurate method. BACTEC was accurate in 92% of cases, whereas the other two assays were accurate in 59% of cases. The mean detection time was 7 days with the BACTEC system versus 28 days with the other two systems (Hoffner 1988).

While BACTEC exemplifies the improvements made in technology aimed at producing speedy, accurate results, it might not be possible for an ill patient to wait even seven days for microbiological confirmation, as treatment should be initiated rapidly when a patient has dMAC. One sensitive but non-specific method is the acid-fast smear, which can detect the presence of mycobacteria within minutes. Acid-fast smears, however, cannot distinguish between Mycobacterium avium complex and Mycobacterium tuberculosis (MTB). Since these two infections differ significantly, a definitive diagnosis is still required. Demographic risk factors and clinical findings vary between the two.

(Kemper 1996)

Polymerase chain reaction (PCR), similar to the technology used to measure viral load in HIV-positive patients, is currently under investigation as a method for direct detection of MAC. PCR technology amplifies MAC DNA from peripheral blood mononuclear cells. Localized and disseminated disease due to Mycobacterium avium, Mycobacterium tuberculosis and Mycobacterium kansasii are relatively common in HIV-positive patients, and their presence in samples can readily be determined by PCR, which can detect as few as 10 Mycobacterium avium organisms in stool samples (Arbeit 1993). PCR's utility in detecting MAC bacteremia is presently being tested in ACTG 865, a sub-study of ACTG 223 (see below).

TREATMENT

Many different single agents and drug combinations have been tested since 1987. One of the first MAC treatment trials examined the effect of clofazimine (100 mg daily) and rifabutin (150-300 mg daily) in HIV-positive patients. While minimal activity (the alleviation of symptoms) was associated with this particular combination, the investigators concluded that significant reductions in MAC bacteremia in peripheral blood is essential for drug efficacy (Masur 1987). When dMAC treatment is not quickly initiated, or is halted, MAC colony counts (the level of MAC in a blood, sputum, stool, or bone marrow sample) rise quickly (Dautzenberg 1991). No treatment or combination of treatments has been shown to completely "eradicate" MAC bacteremia in a majority of treated patients, and treatment must continue for life. Because MAC, like its cousin MTB, quickly develops resistance to any single drug, multiple drug therapy is the standard.

The original standard for dMAC combination therapy was established when the California Collaborative Treatment Group (CCTG) studied a four-drug oral regimen - rifampin (600 mg), ethambutol (15 mg/kg), clofazimine (100 mg once daily), and ciprofloxacin (750 mg twice daily) for 12 weeks. This open-label, non-randomized, phase II, multi-center study enrolled 41 patients who had two consecutive positive MAC cultures and no previous antimycobacterial therapy. With evaluable 31 patients, mean baseline colony counts decreased from 2.1 to 0.7 after 4 weeks (p<0.001). Thirteen (42%) patients became culture negative during therapy, and the mean duration of treatment was 9.7 weeks. Nineteen of 31 (61%) patients completed 12 weeks of therapy (Kemper 1992).

ACTG 135 studied this four-drug regimen alone and in combination with intravenous (IV) amikacin, and found that adding IV amikacin to this established four-drug oral regimen (clofazimine, ciprofloxacin, rifampin, and ethambutol) was no more effective than the four drugs alone. Amikacin added no significant contribution to clinical or microbiologic responses and demonstrated unacceptable toxicity (Parenti 1995).

The Advent of the Macrolides

Therapy against MAC has greatly improved with the introduction of the macrolide antibiotics clarithromycin and azithromycin. Both clarithromycin (500 mg twice daily) and azithromycin (600 mg daily) have demonstrated potent antimycobacterial activity against MAC. Only clarithromycin is approved by the FDA for the treatment of dMAC.

Three studies comparing clarithromycin to placebo have demonstrated clarithromycin to be an effective treatment for dMAC (Dautzenberg 1991; Gupta 1992; Chaisson 1994). ACTG 157 showed that clarithromycin as monotherapy given in doses of 500 to 2000 mg twice daily dramatically reduced levels of bacteremia and demonstrated clinical improvement. It took a median of 4 to 8 weeks for clearance of bacteremia. The lowest dose of 500 mg twice a day was associated with better survival and less GI toxicity. Clarithromycin resistance developed in 21% of the patients within 12 weeks; the rate later climbed to 46% (Chaisson 1994). Some activists objected to the design of this monotherapy study, which demonstrated only transient clinical benefit and selected rapidly for macrolide-resistant MAC.

Two similar azithromycin monotherapy dose-ranging trials showed that azithromycin was effective for the treatment of dMAC with response rates comparable to those seen with clarithromycin (Young 1991; Berry 1993). Significant reductions (but not clearance) of MAC bacteremia were reported in these two trials.

Data from ACTG 157 as well as other studies taught us that clarithromycin or azithromycin monotherapy was associated with a high rate of macrolide resistance and thus a high rate of relapse. According to Richard Chaisson, AResistant organisms usually begin to emerge after two to three months on treatment, and the majority of patients experience relapse with drug-resistant isolates after four or more months on therapy@ (Chaisson 1995).

It was soon apparent that one or more drugs would have to be added to either macrolide in order to prevent resistance and lower the rate of relapse. The U.S. Public Health Service issued guidelines in 1993 for the treatment of dMAC in HIV-positive patients (USPHS 1993) In its updated 1995 guidelines, the USPHS recommended that a combination MAC treatment regimen should include at least two drugs, one of which should be clarithromycin (500 mg twice daily) or azithromycin (500 mg daily). Ethambutol was recommended as the best second drug to add to the macrolide (USPHS 1995).

Ethambutol demonstrated modest activity against dMAC when compared to sparfloxacin and ciprofloxacin (Young 1992). Ethambutol alone at 800 mg daily appeared to be more effective than clofazimine or rifampin in a four week monotherapy study (Kemper 1994).

A third drug was not specifically recommended by the PHS but is often used by clinicians. A number of drugs which have been used as a third agent for dMAC treatment include, amikacin (7.5 mg - 15 mg/kg daily), ciprofloxacin (500-750 mg twice daily), rifampin (10 mg daily), or rifabutin (300 -450 mg daily). Though clinical trials have attempted to discern what regimen is best, studies have found some agents that are not only ineffective but actively harmful.

Advances in MAC Therapy with Macrolide-Containing Regimens

A recent Canadian trial showed that a macrolide-containing three-drug regimen was superior to the four-drug, non-macrolide-containing regimen established by the CCTG and the ACTG. More is not always better! Canadian Trials Network study 010 randomized 229 patients (median CD4 count of 10) with dMAC to receive either a three-drug regimen of clarithromycin, ethambutol, and rifabutin or a four-drug regimen of rifampin, ethambutol, clofazimine and ciprofloxacin (Shafran 1996). Patients were well-matched at baseline, though more patients assigned to three drugs were on PCP prophylaxis, and more assigned to four drugs had a history of PCP.

(Shafran 1996)

Of those who did sterilize their blood, 87% in the three-drug group did so by week 4 as compared with 54% of the patients in the four-drug group (p<0.001). Uveitis - an inflammation of the uveal tract of the eye which may lead to blindness - occurred in 24 of the first 63 patients in the three-drug arm who were administered 600 mg of rifabutin daily. The onset of uveitis occurred at a median of 42 days on rifabutin. Once the elevated incidence of uveitis was recognized, the dose of rifabutin was reduced to 300 mg daily, after which only 3 of 53 patients subsequently developed uveitis. While adjusting the rifabutin dose dramatically decreased uveitis, it also reduced the effectiveness of the original three-drug regimen. For patients in the three-drug group, 41 of 52 (79%) patients achieved clearance of MAC bacteremia before the dose adjustment, whereas 26 of 45 (58%) patients achieved clearance after the adjustment (p=0.008). Moreover, the rates of clearance were significantly higher for those patients originally randomized to the 600 mg dose (p=0.03). Aside from the development of uveitis in the rifabutin patients, there were no significant differences in adverse events, aside from alteration of taste which affected 9 patients in the three-drug group as compared to 1 patient in the four-drug group (p=0.02). The median time to discontinuation of a treatment regimen greatly favored the three-drug group.

Patients on the four-drug regimen survived a median of 65% as long as those on the three-drug regimen (p=0.001) and, by intent-to-treat analysis, the three-drug group had a significant survival advantage (p=0.002). There was no apparent survival difference between the two rifabutin dosing groups. Note, however, the confounding variable of PCP history and prophylaxis at baseline - why were more patients on three drugs receiving PCP prophylaxis, while those on four drugs had a higher history of PCP?

This three-drug regimen is presently being compared to clarithromycin (500 mg twice daily) plus either rifabutin (450 daily) or ethambutol in ACTG 223, a Phase II/III randomized trial. Clarithromycin compliance will be assessed with the Medication Event Monitoring System (MEMS) cap system. ACTG 223 has five sub-studies. ACTG 823 will assess the pharmacokinetic interactions between rifabutin, ethambutol, and clarithromycin. ACTG 824 will study the pharmacodynamic interactions of all three drugs. ACTG 865 will evaluate the use of PCR to detect MAC bacteremia. ACTG 853 will evaluate the effect of treatment for dMAC on pro-inflammatory cytokines and HIV viral load. The fifth sub-study will evaluate the pharmacokinetic interactions among clarithromycin, rifabutin and the protease inhibitors ritonavir and indinavir.

Is Clofazimine Harmful?

Three recent studies have demonstrated that clofazimine provides no clinical or microbiologic benefit for initial therapy and may even be harmful (May 1995; Chaisson 1997; Dube 1997). The French Curavium Study compared two doses of clarithromycin in combination regimens for dMAC. 132 HIV-positive patients (median CD4 count of 14) were randomized to receive a combination of clarithromycin (2000 mg daily for 2 months, then 1000 mg daily) and clofazimine (200 mg daily with a reduction to 100 mg daily) or clarithromycin (same dose), rifabutin (450 mg daily), and ethambutol (1200 mg daily). Success was defined as the patient being alive with decrease of fever and a negative blood culture. All others cases were defined as failure. There was no significant difference in success noted in either group at 2 or 6 months nor was there a difference in survival. As time progressed, however, 18 patients in the two-drug group relapsed with positive dMAC cultures versus 6 in the three-drug group. Moreover, 14 patients in the two-drug group developed clarithromycin resistance as compared with 2 patients in the three-drug group (p=0.001). Thus, clofazimine did not help prolong clarithromycin=s microbiologic activity and led to a faster and more pronounced selection of clarithromycin-resistant strains (May 1995).

The CCTG studied 106 HIV-positive patients with MAC bacteremia for the prevention of relapse of dMAC. Patients were randomized to receive clarithromycin, clofazimine and ethambutol or clarithromycin and clofazimine. With evaluable 80 patients, the clinical and microbiological responses were identical in both groups at a 69% response rate. There were, however, 8 relapses in the two-drug group and 2 relapses in the three-drug group which were all clarithromycin resistant. The estimated risk of relapse at 36 weeks was 68% and 5%, respectively (p=0.004). Moreover, the median time to development of resistance was 16 weeks for the two-drug group and 40 weeks for the three-drug group (p=0.004). Thus, just adding clofazimine to clarithromycin is not enough; resistance and relapse are likely (Dube 1997).

Chaisson and colleagues conducted a similar study comparing clarithromycin and ethambutol with and without clofazimine. While there was no difference in the time to clearance or relapse for either group, survival was significantly decreased in the three-drug clofazimine arm. In fact, 61% of the patients in the three-drug group died, compared with a 38% death rate in the two-drug group (p=0.03), and time to death was shorter in the three-drug group (p=0.01). Unfortunately, patients were not evenly balanced at baseline with regard to the amount of MAC in blood. Those in the clofazimine arm had significantly larger numbers of MAC organisms than those in the two drug arm. Despite this difference, however, a Cox proportional hazard analysis showed that being in the clofazimine treatment arm was still associated with an increased risk of death (Chaisson 1997). Thus, not only is clofazimine suboptimal when added to clarithromycin, but adding it to a multidrug regimen may be harmful to patients. Therefore, the FDA concluded:

Clofazimine adds no measurable bacteriological or clinical benefit to clarithromycin and ethambutol and may result in excessive mortality although the exact mechanism of this is not apparent. It is therefore unwarranted at this time to add clofazimine to clarithromycin and ethambutol for the initial treatment of dMAC. (NIAID/DAIDS Letter to ACTG 223 Investigators).

High-Dose Clarithromycin Leads to Excess Mortality

CPCRA 027 was a MAC treatment study comparing two doses of clarithromycin (500 mg twice a day versus 1000 mg twice a day) in combination with other agents. This study was stopped early because a high mortality rate was observed among those receiving 1000 mg twice a day. As of February 6, 1996, 10 of 45 (22%) patients in the 500 mg arm had died versus 17 of the 40 (43%) patients in the 1000 mg arm (p=0.02). No obvious explanation could be discerned for this increase in mortality, which had also been suggested in two previous MAC treatment trials (Chaisson 1994; Abbott Protocol: M91577, unpublished). After these data emerged, the National Institute Of Allergy and Infectious Diseases (NIAID) sent out a warning that concluded:

The results of the CPCRA MAC Treatment Trial provide further indication that doses of clarithromycin exceeding 500 mg twice daily should not be utilized for the treatment of MAC disease in HIV-infected patients. The explanation for the poorer survival associated with the high dose of clarithromycin compared to the standard dose has not been determined. (NIAID: Letter to Physicians, July 1996)

Clarithromycin or Azithromycin: Which is the Better Drug?

In 1996, the Veteran=s Administration (VA) HIV Consortium Study Group presented preliminary data from a MAC treatment study which compared clarithromycin (500 mg twice daily) and ethambutol to azithromycin (600 mg daily) and ethambutol. While 61 patients enrolled, data were presented on only 29 evaluable patients - 18 patients on clarithromycin and 11 patients on azithromycin. At week 16, 92% (16/18) of the patients in the clarithromycin arm were culture negative as compared with 45% (5/11) of the azithromycin patients (p=0.030). The time to clearance of MAC bacteremia was shorter for the clarithromycin group than for the azithromycin group (4.38 versus 16 weeks) (p=0.0018) (Ward 1996). While these provocative data appear to suggest that clarithromycin may be better, little can be garnered from such a small study with uneven randomization. Follow-up data from all VA patients as well as from Pfizer=s large, randomized, comparative study are needed before the winner can be declared.

PROPHYLAXIS

Three drugs are currently FDA-approved drugs for the prophylaxis of MAC infection: rifabutin, clarithromycin and azithromycin. In 1993, the United States Public Health Service (USPHS) recommended that rifabutin be initiated in HIV-positive patients with fewer than 100 CD4 cells for the prevention of MAC (USPHS 1993). In 1995, the CDC, in conjunction with the PHS and the Infectious Disease Society of America (IDSA) revised the guidelines recommending that HIV-positive patients with fewer than 75 CD4 cells initiate rifabutin (300 mg daily) as the first-line agent for the prevention of MAC and use clarithromycin (500 mg twice daily) as the second-line agent (USPHS 1995). Since then, however, a number of randomized, controlled studies have been presented or published demonstrating that the macrolides clarithromycin or azithromycin, alone, are more effective than rifabutin alone and no more effective and less toxic than combining rifabutin with clarithromycin as prophylaxis against MAC (Benson 1996; Havlir 1996; Pierce 1996). In light of these data, the 1997 USPHS/IDSA panel recommended MAC prophylaxis with either clarithromycin or azithromycin be initiated in patients with CD4 counts below 50 (USPHS 1997).

Rifabutin (MycobutinTM, Pharmacia & Upjohn)

Two placebo-controlled studies conducted by Nightingale and colleagues (Nightingale 1993) found that rifabutin effectively delays MAC bacteremia in HIV-positive persons with fewer than 200 CD4 cells; median follow-up on randomized study drug was eight months.

Rifabutin Prevents MAC Bacteremia
Study	Median CD4	Rifabutin	Placebo	p-value
Nightingale 1	61	24/292 (8%)	51/298 (17%)	<0.001
Nightingale 2	58	24/274 (9%)	51/282 (18%)	<0.002

There were no significant differences in the rate of adverse events. Neutropenia was consistently associated with rifabutin use. No survival benefit was apparent after eight months of follow-up (Nightingale 1993). Subsequently, the incidence of MAC went up to 20% after two years. While both studies proved that rifabutin was better than placebo at preventing MAC bacteremia, many physicians were not convinced there was significant clinical benefit. For a number of reasons, then, the 1993 PHS guidelines were not widely accepted: 1) no survival benefit was seen; 2) subsequent data revealed an increased risk of the development of uveitis in patients receiving over 300 mg of rifabutin daily (Shafran 1994; Frank 1994; Fuller 1994; Havlir 1994); 3) rifabutin=s potential to select for rifampin resistance in patients with concurrent tuberculosis; 4) rifabutin's complex interactions with many other drugs; and 5) its high cost (Pierce 1995).

A subsequent post hoc analysis of the rifabutin studies demonstrated that, with longer follow-up, rifabutin use was associated with improved survival. Data from all 1,146 patients included in the double-blind studies and who continued on open-label follow-up were used in this on-treatment analysis. When adjustments were made for Karnofsky score, occurrence of opportunistic infections and for use of rifabutin as a time-dependent variable, the relative hazard (RH) of dying for those in the rifabutin group was 0.74, representing a 26% reduction in the hazard of death for the entire cohort (p<0.004). For the rifabutin patients with CD4 counts below 50 at baseline (N=655), the RH of dying was 0.75 [95% confidence interval (CI), 0.58-098], and for the rifabutin patients with CD4 counts above 50 at baseline (N=491), the RH of dying was 0.69 (95% CI, 0.49-0.99) (Moore 1995).

Drug interactions between rifabutin and many other anti-HIV medications pose complicated management issues in patient management. Unlike the classic nucleoside analogues (AZT, ddI, ddC, d4T, and 3TC), which do not interfere with the metabolism of many other drugs, most protease inhibitors are metabolized by the cytochrome P450 enzyme system of the liver, the same enzyme system responsible for metabolizing rifabutin, and which rifabutin induces to increase the metabolism of other drugs. For example, if rifabutin is taken with saquinavir, which already suffers from poor oral bioavailability, saquinavir levels in the blood will be reduced to near zero. On the other hand, if rifabutin is taken with ritonavir, rifabutin levels will be dramatically increased. Combining indinavir and rifabutin increases rifabutin levels and decreases indinavir levels, but the magnitude of these changes is not as great as with ritonavir.

Clarithromycin (BiaxinTM, Abbott Laboratories)

Clarithromycin has been shown to prevent MAC and reduce mortality in an Abbott-sponsored, randomized, double-blind, placebo-controlled study of HIV-positive patients with fewer than 100 CD4 cells. In this study, 682 patients with negative MAC blood cultures from 66 centers in the US and Europe were randomized to receive 500 mg of clarithromycin twice daily or placebo. Median baseline CD4 count was 27.5, and follow-up ten months.

All 64 patients who developed dMAC had a CD4 count of below 50, with 50% of them below 10. Patients in the clarithromycin group had an estimated 69% reduction in the risk of developing dMAC, with an adjusted HR of 0.31 (95% CI, 0.18-0.53). Interestingly, the risk reduction documented in the clarithromycin group was smaller in the US patients (60%) than in the European patients, and dMAC developed in 21% US placebo patients versus 11% of the European placebo patients. This was the first prospective MAC prophylaxis study to document a survival benefit. The estimated relative hazard for mortality for clarithromycin, compared to placebo, was 0.75 (95% CI, 0.58-0.97) which constitutes a 25% difference in mortality favoring the clarithromycin patients. With regard to causes of death, there was no significant difference between the treatment groups. Rates of discontinuation of study drug due to adverse events were similar in both groups: 8% for clarithromycin versus 6% placebo (p=0.45).

Clarithromycin Prevents MAC Bacteremia
	Clarithromycin	Placebo	p-value
MAC bacteremia	19/333 (6%)	53/334 (16%)	<0.001
Hazard ratio (C/P)	0.31	1.0
Mortality	107/333 (32%)	137/334 (41%)	<0.026
Median survival	700 days	573 days
Hazard ratio (C/P)	0.75	1.0
GI disturbance	28%	18%	0.004
Taste disturbance	8%	0.3%	<0.001

(Pierce 1996)

Among the 19 clarithromycin patients who developed dMAC, 58% (11 patients, with a median CD4 count of 10) were found to have clarithromycin-resistant MAC isolates, defined as a minimum inhibitory concentration (MIC) of greater than or equal to 512 micrograms per milliliter. While approximately 58% of the isolates recovered from clarithromycin patients who developed dMAC (11 out of 19) were clarithromycin-resistant, only 3.5% of the 333 clarithromycin patients broke through with a resistant isolate. Some have misinterpreted the resistance findings from this study, suggesting that half the patients who use clarithromycin for MAC prophylaxis will become resistant. Data from the study do not suggest that widespread resistance will occur with clarithromycin use.

Clarithromycin versus Rifabutin versus Both

ACTG 196/CPCRA 009 compared three prophylactic regimens for the prevention of dMAC: clarithromycin monotherapy (500 mg twice daily), rifabutin monotherapy (450 mg once daily) versus the combination in HIV-infected patients with CD4 counts below 100. 1,216 patients were enrolled, and 1,178 were eligible for analysis. The median baseline CD4 count was 27 and median follow-up was 589 days. In February 1995, the rifabutin dose was reduced to 300 mg daily to decrease the risk of uveitis.

ACTG 196/CPCRA 009: Clarithromycin vs. Rifabutin vs. Both for MAC Prophylaxis
	Clari/Rif	Clarithromycin	Rifabutin	p-value
dMAC	26/389 ( 7%)	35/398 (9%)	59/391 (15%)	<0.05
Mortality	179/389 (46%)	167/398 (42%)	168/391 (43%)	NS
Discontinued due to toxicity	120/389 (21%)	63/398 (16%)	71/391 (18%)	<0.05
GI pain	2.0%	4.9%	4.5%
Uveitis	5.7%	0.5%	1.2%

(Benson 1996)

While combination therapy and clarithromycin alone were clearly superior to rifabutin monotherapy in preventing dMAC, there was no statistically significant difference in survival.

Susceptibility testing was conducted on isolates obtained from many patients who developed dMAC. Resistance to clarithromycin (a minimum inhibitory concentration, or MIC, of 32 micrograms per milliliter) was documented in 0% of rifabutin isolates, 7 of 24 (29%) clarithromycin isolates, and 4 of 16 (25%) combination isolates. Thus, the actual rate of clarithromycin resistance for the 398 patients assessed from the clarithromycin arm was approximately 2%. It is important to note that the 25 to 29% clarithromycin resistance rate among clarithromycin patients who broke through was less than the 58% rate documented in the placebo-controlled clarithromycin study of Pierce and colleagues. While the resistance rate seen in the clarithromycin arm of ACTG 196/CPCRA 009 was not particularly alarming, the rate documented in the combination arm was disappointing. Some had expected that combining both drugs would significantly reduce the rate of clarithromycin resistance. Nevertheless, adding a less potent drug to clarithromycin did not significantly decrease breakthroughs or ameliorate resistance, it just caused more toxicity.

Azithromycin (ZithromaxTM, Pfizer)

Azithromycin - a sister macrolide of clarithromycin - was compared with placebo in a randomized, double-blind MAC prophylaxis trial sponsored by Pfizer in which 182 patients with fewer than 100 CD4 cells (median 44) were randomized to receive once-weekly azithromycin (1200 mg) or placebo and followed for about one year:

Azithromycin Prevents MAC Bacteremia
	Azithromycin	Placebo	p-value
dMAC	7/85 (8.2%)	20/86 (23.3%)	0.002
GI disturbance	83%	44%

(Oldfield 1996)

In an on-treatment analysis that included events up to 30 days after the last dosing of both drugs, 10.6% of azithromycin patients developed MAC, as compared to 24.8% of the placebo recipients. The small sample size in this study did not allow for the determination of a survival benefit with azithromycin. The primary adverse events associated with azithromycin use in this study were GI disturbances (nausea, vomiting, diarrhea). Azithromycin versus Rifabutin versus Both Havlir and colleagues from the California Collaborative Treatment Group (CCTG) compared azithromycin (1,200 mg weekly) to rifabutin (300 mg daily) to a combination of both in 669 HIV-infected persons with CD4 counts less than 100. Patients had median CD4 counts of 36, 38, and 45, respectively and were followed for a median of 514 days.

Azithromycin vs. Rifabutin vs. Both for MAC Prophylaxis Azi/Rif Azithromycin Rifabutin p-value Got MAC Intent-to-treat 18/218 (8.3%) 31/223 (13.9%) 52/223 (23.3%) Azi/Rif vs. Rif <0.001 Azi vs. Rif 0.02 On-treatment 5/199 (2.5%) 18/204 (8.8%) 24/204 (11.8%) Not given Mortality 81/218 (37%) 83/223 (37%) 85/223 (38%) NS GI toxicity 74% 84% 56% <0.001 Dose-limiting toxicity 23% 13% 16% 0.001 Developed PCP 8.5% 8.3% 13.3% 0.034

(Havlir 1996)

The investigators adjusted for baseline CD4 values and stratified by center and prophylaxis for fungal infections (for which a substudy was comparing weekly versus daily fluconazole).

Risk for dMAC in CCTG Azithromycin/Rifabutin Study Hazard Ratio (HR) with 95% Confidence Interval (CI) Comparison On-treatment analysis Intent-to-treat p-value Azithromycin vs. Rifabutin 0.63 (0.33, 1.21) 0.53 (0.34, 0.85) 0.008 Combination vs. Rifabutin 0.17 (0.05, 0.46) 0.23 (0.10, 0.49) <0.001 Combination vs. Azithromycin 0.27 (0.10, 0.74) 0.53 (0.29, 0.95) 0.03

(Havlir 1996)

By intent-to-treat analysis, combination therapy reduced the risk of dMAC by 77% versus rifabutin alone and by 47% versus azithromycin alone. Azithromycin alone reduced the risk of dMAC by 47% compared with rifabutin alone. Time to death did not differ significantly among the three arms (Havlir 1996).

Forty-seven isolates from patients who developed MAC were tested for macrolide resistance. Two of 18 (11%) isolates from azithromycin patients were found to be resistant to azithromycin (MIC greater than 256 micrograms per milliliter) and clarithromycin (MIC greater than 16 micrograms per milliliter). None of the 21 isolates obtained from rifabutin patients and none of the 5 isolates from combination therapy patients were found to harbor macrolide resistance. The rate of macrolide resistance for all patients randomized to azithromycin was approximately 1%.

Interestingly, a sub-study of the CCTG trial suggested that azithromycin may help augment PCP prophylaxis. While 95% of all patients were receiving PCP prophylaxis (58% on Bactrim; 18% on dapsone; 19% on aerosolized pentamidine) 13.3% of the rifabutin patients developed PCP versus 8.3% and 8.5% in the azithromycin and combination arms, respectively (p=0.045 and 0.034, respectively). Thus, adding azithromycin to PCP prophylaxis regimens appears to reduce the risk of developing PCP by almost one half in a majority of patients with fewer than 50 CD4 cells (Dunne 1996). We will know whether clarithromycin confers similar benefits when the final analysis of ACTG 196 is complete.

Should MAC Prophylaxis be Used?

Despite the 1997 USPHS/IDSA guidelines recommending MAC prophylaxis for all patients with fewer than 50 CD4 cells, many clinicians still do not routinely offer prophylaxis, assuming that it is more effective to monitor sputum, stool, or blood values for bacteremia on a regular basis, using acid-fast smears, radiographic assessments, or the newer PCR technology, rather than to place everyone with under 50 CD4 cells on prophylactic therapy.

However, the ability of multiple MAC prophylaxis regimens to delay disseminated MAC disease and prolong survival should convince clinicians to use MAC prophylaxis routinely, at least among patients with fewer than 50 CD4 cells. The survival benefit documented in the clarithromycin placebo-controlled study should be convincing enough. Moreover, in the clarithromycin and azithromycin studies, both macrolides proved to have a protective effect against many bacterial infections which can cause significant morbidity in patients with advanced HIV disease (Pierce 1996; Benson 1996; Oldfield 1996; Havlir 1996).

What Should be Used for First-line MAC Prophylaxis?

This question has been discussed thoroughly since data became available from ACTG 196 and the CCTG study. Both studies indicate that rifabutin should no longer be used for first-line MAC prophylaxis because both macrolides were more effective. Comparisons between azithromycin and clarithromycin cannot be made since they have never been studied head-to-head for MAC prophylaxis. Nonetheless, variables can be considered when deciding on which drug to use.

Which Drug Should Be Used for First-Line MAC Prophylaxis? Variable Drug Comments Efficacy in preventing dMAC Clarithromycin or Azithromycin MAC incidence rates similar, though clarithromycin studies had longer follow-up. Survival Clarithromycin Pierce et al. is the only prospective, randomized study with a clear survival benefit. Tolerability Azithromycin Once-weekly dosing more attractive than alternatives Resistance Azithromycin or Clarithromycin Rifabutin <1% in Havlir 1996; ~2% in ACTG 196; clarithromycin studies have longer follow-up, so there may be little difference Resistance not documented; less effective prophylaxis; saves macrolides for treatment Cost Azithromycin Cost per case prevented (McCutchan 1996): Azithromycin $ 9,617 Clarithromycin $16,940 Rifabutin $19,842 Drug interactions Azithromycin or Clarithromycin Interactions with protease inhibitors not well-characterized

(Constance Benson, personal communication)

Should MAC Prophylaxis Ever Be Stopped?

Some primary care physicians, prison doctors, and HMO clinicians are taking patients on PPICT off their MAC prophylaxis if their CD4 counts increased above 50. This continues to occur even though last year the USPHS/IDSA OI prophylaxis guidelines panel recommends "continuing prophylaxis based on the nadir (the lowest) of a patient's CD4 count." (USPHS 1997)

In order to test whether stopping OI prophylaxis is sound or harmful in patients whose CD4 counts have risen above a certain threshold, Currier and colleagues developed ACTG 362, the first "stop MAC prophylaxis" trial. ACTG 362 is a randomized, double-blind, placebo-controlled trial available to any PWA who is receiving antiretroviral therapy and has had a documented increase in CD4 cell count from below 50 on one occasion to above 100 on two separate occasions, sequentially, at least four weeks apart. 636 patients will enroll. Participants will be randomized to receive azithromycin 1200 mg once weekly or matching placebo and will be followed closely every eight weeks for 18 months. Patients whose CD4 count drops below 50 on two measurements at least four weeks apart will be offered open-label azithromycin. All patients will be stratified at baseline for prior use of MAC prophylaxis into three groups: no prophylaxis, prior azithromycin prophylaxis and other MAC prophylaxis (ACTG 362).

FUTURE DIRECTIONS IN MAC RESEARCH

Basic and clinical research should focus on the pathogenesis of MAC in which the relationship between cytokine abnormalities (and which cytokines) and MAC infection can be defined. With this knowledge, we might want to address whether the manipulation of the immune system, either indirectly with exogenous IL-12 or directly with gamma interferon, will improve the host response to MAC infection. Likewise, G-CSF and GM-CSF - both in clinical trials for MAC - might hold some promise.

With regard to treatment, we should strive to define optimal therapy for prolonged disease-free survival. In this attempt, we will want identify factors associated with the development of macrolide resistance, whether they be subtherapeutic drug levels, polyclonal infection, or failure of the immune system. It is essential that industry, along with the NIH, work to identify and develop new anti-MAC compounds.

Research directed at MAC prophylaxis should continue to evaluate new assays using MAC antigens and PCR to determine those most at risk. If we can determine those most at risk - or those with asymptomatic infection - strategies concerning "pre-emptive therapy" should be discussed.

*

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